Conjugates for dual imaging and radiochemotherapy: composition, manufacturing, and applications

Abstract

Compositions and methods for dual imaging and for dual chemotherapy and radiotherapy are disclosed. More particularly, the invention concerns compounds comprising the structure X 1 —Y—X 2 , wherein Y comprises two or more carbohydrate residues covalently attached to one another, X 1 and X 2 are diagnostic or therapeutic moieties covalently attached to Y, provided that when Y does not comprise a glucosamine residue, X 1 and X 2 are diagnostic moieties. The present invention also concerns methods of synthesis of these compounds, application of such compounds for dual imaging and treatment of hyperproliferative disease, and kits for preparing a radiolabeled therapeutic or diagnostic compound.

1 .- 2 . (canceled) 
     
     
         3 . The method of  claim 60 , wherein Y comprises poly(glucosamine). 
     
     
         4 .- 6 . (canceled) 
     
     
         7 . The method of  claim 3 , wherein the compound is of formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is a therapeutic moiety or diagnostic moiety, R 2  is a chelator moiety; and 
         wherein n is an integer of 1 or greater; or a stereoisomer of (I), or a combination of stereoisomers of (I), or a pharmaceutically acceptable salt of (I). 
       
     
     
         8 . The method of  claim 7 , wherein n is 2 to 2000. 
     
     
         9 . The method of  claim 8 , wherein n is 50 to 500. 
     
     
         10 . The method of  claim 60 , wherein at least one of R 1  or R 2  is a chelator moiety. 
     
     
         11 .- 12 . (canceled) 
     
     
         13 . The method of  claim 10 , wherein the chelator moiety is selected from the group consisting of an N 4  compound, an N 2 S 2  compound, DTPA, DMSA, EDTA, Cy-EDTA, EDTMP, DTPA, CyDTPA, Cy2DTPA, BOPTA, DTPA-MA, DTPA-BA, DTPMP, DOI′A, TRITA, TETA, DOTMA, DOTA-MA, HP-DO3A, pNB-DOTA, DOTP, DOTMP, DOTEP, DOTPP, DOTBzP, DOTPME, HEDP, DTTP, an N 3 S triamidethiol (MAG3), DADS, MAMA, DADT, a diaminetetrathiol, an N 2 P 2  dithiol-bisphosphine, a 6-hydrazinonicotinic acid, a propylene amine oxime, a tetraamine, a cyclal, and a cyclam. 
     
     
         14 . The method of  claim 13 , wherein the chelator moiety is ethylenedicysteine. 
     
     
         15 . The method of  claim 10 , further comprising a valent metal ion attached to the chelator moiety. 
     
     
         16 . The method of  claim 15 , wherein the valent metal ion is selected from the group consisting of Tc99m, Cu-60, Cu-61, Cu-62, Cu-67, In-111, Tl-201, Ga-67, Ga-68, As-72, Re-186, Re-188, Ho-166, Y-90, Sm-153, Sr-89, Gd-157, Bi-212, and Bi-213. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 60 , wherein at least one of the imaging moieties is a contrast media. 
     
     
         19 . The method of  claim 18 , wherein the contrast media is selected from the group consisting of a CT contrast media, an MRI contrast media, and optical contrast media, and an ultrasound contrast media. 
     
     
         20 . The method of  claim 19 , wherein the contrast media is a CT contrast media selected from the group consisting of iothalamate, iohexol, diatrizoate, iopamidol, ethiodol, and iopanoate. 
     
     
         21 . The method of  claim 18 , wherein the compound is of formula (II): 
       
         
           
           
               
               
           
         
         wherein n is an integer that is one or greater; 
         or a stereoisomer of (II), or a combination of stereoisomers of (II), or a pharmaceutically acceptable salt of (II). 
       
     
     
         22 .- 23 . (canceled) 
     
     
         24 . The method of  claim 19 , wherein the contrast media is an MRI contrast media. 
     
     
         25 . The method of  claim 24 , wherein the MRI contrast media is an MRI contrast media selected from the group consisting of a gadolinium chelate, a manganese chelate, a chromium chelate, and iron particles. 
     
     
         26 . The method of  claim 19 , wherein the contrast media is an optical contrast media. 
     
     
         27 . The method of  claim 26 , wherein the optical contrast media is selected from the group consisting of fluorescein, a fluorescein derivative, indocyanine green, Oregon green, a derivative of Oregon green derivative, rhodamine green, a derivative of rhodamine green, an eosin, an erythrosin, Texas red, a derivative of Texas red, malachite green, nanogold sulfosuccinimidyl ester, cascade blue, a coumarin derivative, a naphthalene, a pyridyloxazole derivative, cascade yellow dye, and dapoxyl dye. 
     
     
         28 . The method of  claim 19 , wherein the contrast media is an ultrasound contrast media. 
     
     
         29 . The method of  claim 28 , wherein the ultrasound contrast media is selected from the group consisting of perfluorine or an analog of perfluorine. 
     
     
         30 .- 37 . (canceled) 
     
     
         38 . The method of  claim 60 , wherein the compound is further defined as an imaging agent suitable for imaging using PET or SPECT. 
     
     
         39 . The method of  claim 60 , wherein the compound firth comprises a tissue-targeting ligand. 
     
     
         40 .- 59 . (canceled) 
     
     
         60 . A method of imaging a subject, comprising:
 a) administering to the subject a composition comprising a diagnostically effective amount of a compound comprising the structure:
   X 1 —Y—X 2  
 
 wherein Y comprises at least two carbohydrate residues covalently attached to one another, and X 1  and X 2  are diagnostic moieties covalently attached to separate carbohydrate moieties of Y; and 
   b) performing imaging using a first imaging modality by detecting a first signal from X 1  diagnostic moieties of said compound; and   c) performing imaging using a second imaging modality by detecting a second signal from X 2  diagnostic moieties of said compound,   
       wherein the first imaging modality and the second imaging modality are performed either concurrently or consecutively. 
     
     
         61 . The method of  claim 60 , wherein Y comprises poly(glucosamine) a poly(glucosamine) analog, chitin, a chitin analog, chitosan, a chitosan analog, heparin, or a heparin analog. 
     
     
         62 . (canceled) 
     
     
         63 . The method of  claim 60 , wherein the first imaging modality and the second imaging modality are different imaging modalities, each separately selected from the group consisting of PET, CT, SPECT, MRI, optical imaging, and ultrasound. 
     
     
         64 .- 78 . (canceled)